The invention relates to a method for preparing a 2,5-disubstituted pyridine and novel intermediates.
PCT Application WO 02/10172 discloses novel azabicyclic compounds useful as drugs in the anti-bacterial field and their preparation using intermediate compounds of formula (A):
wherein R′1, R′2, R3, Z and n are as defined in said application, and notably among these intermediate compounds, a piperidine of formula (A1):
corresponding to a compound of formula (A) wherein n=1 and A′=CH2.
Among the compounds of formula (A1), the compound with the following formula (I) is of particular interest:
wherein                P1 and P2 represent protecting groups of carboxylic acid and oxyamine functions,known to those skilled in the art, and notably those mentioned in PCT Application WO 02/10172.        
The compound of formula (I) is in the form of a mixture of isomers (2S,5R) and (2S,5S). The compound of formula (I) may be obtained as described in PCT Application WO 02/10172, notably in Example 32, starting from protected cis-5-hydroxy-piperidine-2-carboxylic acid.
The object of the present invention is a novel method for preparing the compound of formula (I), characterized in that the compound of formula (b):
                wherein P1 and P3 represent protecting groups of the carboxylic acid function and of the nitrogen,is treated by a HCl generating reagent, in order to obtain the compound of formula:        
                wherein P1 and P3 are defined as here above,which is treated, without being isolated, with a hydroxylamine derivative, in order to obtain the compound of formula:        
wherein P1 and P3 are defined as here above and P2 represents a protecting group of the oxime, the amine of which is deprotected by the action of an acid, in order to obtain the compound of formula:
                wherein P1 and P2 are as defined here above,which is cyclized by the action of a base in order to obtain the compound of formula:        
                wherein P1 and P2 are defined as here above,the oxime function of which is reduced by the action of a reducing agent, in order to obtain the expected compound of formula (I) which, if desired, is put in the form of a salt by the action of an acid.        
The beta-ketosulfoxonium compound of formula (b) may be obtained starting with the protected (S) pyrroglutamic acid of formula (a):
                wherein P1 and P3 are defined as here above,the ring of which is opened by the action of trimethylsulfoxonium iodide in the presence of sodium hydride in tetrahydrofurane.        
The protecting group of the carboxylic acid function P1 is notably an alkyl, allyl, benzyl or p-nitrobenzyl ester residue; equivalent residues known to those skilled in the art may of course also be suitable. P1 preferably is a benzyl group. The protecting group of the nitrogen P3 notably forms a carbamate and preferably is a tert-butoxycarbonyl or benzyloxycarbonyl group, it may also be an electro-withdrawing group such as those known to one skilled in the art and referenced in “Greene” (Protective Groups in Organic Synthesis, 3rd edition). P3 preferably is a tert-butoxycarbonyl group.
The protecting group of the hydroxylamine P2 is notably a benzyl or allyl residue. P2 preferably is a benzyl group.
The conditions generating HCl and allowing preparation of the compound of formula (II) preferably consist of using lithium chloride in the presence of a strong acid. Hydrochloric acid may also simply be used. The strong acid is for example hydrochloric acid, sulfuric acid, sulfonic acid such as methane sulfonic acid or ethane sulfonic acid. According to a preferred condition of carrying out the invention, lithium chloride is used in the presence of methane sulfonic acid. This is performed for example within an ether such as tetrahydrofurane or dioxane, within dimethylsulfoxide or within an ester such as ethyl acetate. The protection of the ketone function of the compound of formula (II) is achieved without isolation of the intermediate, depending on the selected protective group, under conditions known to those skilled in the art.
Deprotection of the amine function is achieved by the action of an acid, for example hydrochloric acid, sulfonic acid, trifluoroacetic acid or an alkane sulfonic acid. Depending on the nature of the protective group, these conditions are known to one skilled in the art. Advantageous conditions consist of using a tert-butoxycarbonyl group and of cleaving it by the action of methane sulfonic acid. This may be performed for example in ethyl acetate.
The protected α-chlorooxime of formula (III) is preferably used without being isolated, i.e. in solution in the reaction solvent. The same applies for the protected α-chlorooxime of formula (IV). The base used for cyclizing the compound of formula (IV) is for example an alkaline hydroxide, carbonate or bicarbonate, preferably sodium bicarbonate, or a base of the amine type, for example triethylamine. The reducing agent used for reducing the oxime function is for example a reagent of the alkaline borohydride, diborane or borane-pyridine type in the presence of an acid, for example hydrochloric acid. This may be performed within an alcohol such as methanol or ethanol, or within another organic solvent such as dichloromethane.
The salification of the compound of formula (I) is, if necessary, achieved by adding to the compound an acid in a soluble phase. Among the salts of the acids used for obtaining the products of formula (I), mention may be made, inter alia, to those formed with inorganic acids, such as hydrochloric, hydrobromic, hydroiodic, sulfuric or phosphoric acids, or with organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfonic acids, such as methane and ethane sulfonic acids, arylosulfonic acids such as benzene- and paratoluene-sulfonic acids. The salts are preferably those which allow easy crystallization. The oxalic acid salt is particularly preferred.
Compounds of the type (a) and (b) as well as of the type (II) the formulae of which are indicated above, are known, and mention may be made to the articles of J. Chem. Soc. Chem. Comm. 1993, p. 1434-1435 and Tet. Letters Vol. 29, No. 18, p. 2231-4 (1988). Steps aimed at cyclizing the compounds (B) and (II) were tried.
Cyclization of compound (b) is possible but involves the use of a rhodium-based reagent. Application of this type of reagent on an industrial scale is not a very practical proposition and is very costly. Further, the yields obtained are not satisfactory. Alternatives to rhodium have been sought unsuccessfully.
Cyclization of compound (II) was however unable to be achieved, probably due to the reactivity of the carbonyl group. The present invention provides a method for preparing the intermediate formula (I) under particularly attractive conditions, with an overall yield of the order of 70% and which therefore allows the failure encountered earlier to be overcome. The compounds of formula (III), (IV) and (V) obtained using the method are novel and also constitute a subject matter of the invention, as novel industrial compounds and notably intermediate compounds required for preparing the compounds of formula (I).